Project Summary/Abstract In the classical approach to immunization against viral diseases, viral proteins are delivered or expressed in the vaccine recipient and it is hoped that the resultant immune responses are protective. For a variety of reasons, such a classic approach faces severe obstacles to success against HIV-1. The Desrosiers laboratory has been investigating a nonclassical approach by which a viral vector, adeno-associated virus (AAV), is used to achieve very long-term delivery of anti-HIV monoclonal antibodies (mAbs) with potent neutralizing activity against a broad spectrum of HIV-1 isolates. AAV vectors have proven safe in human testing and are currently the vector of choice for correction of hereditary enzyme/metabolism deficiencies. When delivered intramuscularly, transgene expression can continue for years, decades, probably for life, as long as the transgene product is not viewed as foreign. The vision is that a single inoculation of AAV vector making a cocktail of potent broadly-neutralizing antibodies will provide sterilizing immunity for the rest of the individual's life. Although an antibody may be viewed as a ?self? protein, studies in monkeys have revealed that a host antibody response may occur to the delivered mAb and this may severely limit the concentration of mAb that can be achieved. The Desrosiers laboratory will continue its progress toward minimizing the anti-anti problem and achieving consistent delivery of desirable antibodies using rhesus monkey models. These studies are directly targeted to facilitating development of this concept for use in humans.